The increasing global incidence of systemic fungal infections may largely be attributed to advances in medical technology and organ transplantation, an increase in the prevalence of cytotoxic chemotherapeutic interventions, the widespread use of broad spectrum antimicrobials and an increasing number of immunocompromised patients.
The most common causes of these infections are due to Candida spp., of which C. albicans accounts for approximately 50% and filamentous fungi such as Aspergillus spp. (Kremery and Barnes, 2002). Mortality associated with invasive Candida ranges from around 40% (Edmond et al., 1999), while mortality associated with invasive Aspergillus approaches 100% in solid organ transplant recipients (Minari et al., 2002).
Given the lack of readily available fungal vaccines, the only clinical resource available to combat fungal infections is antifungal therapeutics (antimycotics). The antimycotics currently in clinical use are limited either by their general ineffectiveness and inadequate pharmacological profile, including undesired drug-drug interactions and narrow activity spectrum, their fungistatic nature, or by their high overall cytotoxicity (White et al., 1998). Accordingly, there is a critical need for new antifungal compounds that could overcome these disadvantages.
Zhang et al. recently reported the formation of a 1:1 adduct of the antifungal azole compound miconazole nitrate with 2,6-di-tert-butyl-4-methylphenol (BHT) (Zhang et al., 2004). The present invention relates in part to the unexpectedly enhanced antifungal activity exhibited by this adduct as well as by adducts of BHT with other azole compounds and adducts of compounds of formula (I) other than BHT with miconazole nitrate and other azole compounds.